This K99/R00 award will be integral in the development of Dr. Morris' career plan, which was designed to extend her pre-doctoral preclinical training in neurodegenerative disease and metabolism to human subjects research. Dr. Morris has shown her ability to make this transition in her F32 NRSA project, which allowed her to implement the hyperinsulinemic-euglyecmic clamp procedure, the gold standard for measuring insulin resistance, in healthy elderly, preclinical Alzheimer's Disease (AD), and AD subjects. While Dr. Morris has received training in clinical research over the past 2 years, she needs additional advanced training in AD methodology (specifically neuroimaging), and additional metabolic measures. While the hyperinsulinemic- euglycemic clamp is optimized for measuring insulin resistance, it does not measure hormone secretion, and this project will allow Dr. Morris to obtain training in a physiologically-relevant method of measuring insulin secretion, the mixed meal tolerance test. Moreover, it will allow Dr. Morris to make translational observations, linking cellular bioenergetics in individual subjects with clinical physiological and imaging outcomes. Dr. Morris will work in the department of Neurology at the University of Kansas Medical Center (KUMC) under the mentorship of Dr. Jeffrey Burns. Dr. Morris will capitalize on several of KUMC's research strengths: the Hoglund Brain Imaging Center, the NIH-designated Alzheimer's Disease Center, and the Clinical and Translational Science Unit (funded through an NIH CTSA). The proposed additional training will allow her to effectively compare metabolic hormone secretion in healthy aging and AD, the relationship with brain structure, and mechanisms that could be driving metabolic dysregulation, including genetics and mitochondrial dysfunction. In order to ask more complex questions about the role of metabolism (specifically, meal induced secretion of pancreatic and GI secreted hormones) in aging and AD, she will need additional mentored training in metabolic analyses under physiologist Dr. John Thyfault, cellular bioenergetics under Dr. Russell Swerdlow, Director of the KU Alzheimer's Disease Center and Professor of Neurology at KUMC, and imaging measures (MRI) under Dr. Burns. The combination of well-funded and experienced mentors, education, and clinical research experience provides an ideal vehicle for advancing Dr. Morris' career goals. Dr. Morris' overall goal is to build upon her previous work by investigating specific mechanisms of insulin resistance in AD, including dysregulated metabolic hormone secretion and bioenergetic dysfunction. We will use the most physiologically-relevant method of measuring pancreatic function, the mixed meal tolerance test, which will allow simultaneous measurement of beta cell function, incretin hormone secretion, and insulin resistance. These results will be related to mitochondrial function and characterized in terms of longitudinal measures of decline, including brain atrophy and cognitive trajectory.